POS0754 PROTEASOME ACTIVITY TEST AS A POTENTIAL CLINICAL TOOL FOR THE DIAGNOSIS OF CHRONIC ATYPICAL NEUTROPHILIC DERMATOSIS WITH LIPODYSTROPHY AND ELEVATED TEMPERATURE (CANDLE) SYNDROME AND RELATED PROTEASOME DISORDERS
Authors: Y. Levinsky, O. Scheuerman, R. Tal, G. Amarilyo, L. Harel
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, is an interferonopathy caused by proteasomal dysfunction. Clinical characteristics include early onset inflammation, nodular rashes, hepatosplenomegaly, myositis, panniculitis, lipodystrophy and basal ganglion calcifications. CANDLE and associated syndromes are gouped into the proteasome-associated autoinflammatory syndromes (PRAAS). Our patient presented at age of 3 months with features strongly suggestive of PRAAS. Genetic testing revealed a novel proteasome variant classified as a variant of unknown significance (VUS). <h3>Objectives</h3> Functional testing of the proteasome was undertaken in order to support the suspicion of PRAAS. Our aims are to describe the potential role of this test for aiding in the diagnosis of PRAAS. <h3>Methods</h3> First, interferon signature was obtained and whole exome sequencing was analyzed for the patient and her parents. Nest, samples of whole blood were taken from the patient, parents and 3 healthy controls. PBMC were lysed using activity preserving methods (active extraction). Samples were normalized using BCA enzymatic assay. Activity of the proteasomal subunits was measured using peptides specific to different subunits (caspase, chymotrypsin and trypsin activity). <h3>Results</h3> Interferon signature was abnormally high, suggestive of an interferonopathy. Whole exome sequencing revealed a novel heterozygous variant in a PSMB4, the gene that encodes for β7, a structural non –catalytic subunit of the proteasome classified as a variant of unknown significance (VUS). A pilot analysis of proteasome activity showed a 50% reduction in the catalytic activity of proteasome subunit β1, indicating severe impairment of proteasomal activity, with compensatory hyper-activation of the immunoproteasome subunit β1i (Figure 1). The apparent dysfunction of β1 and hyper activation of β1i suggested a proteasomal assembly dysfunction. Using the above findings, the patient commenced JAK inhibitor (baricitinib) with remarkable clinical improvement (Figure 2). <h3>Conclusion</h3> Proteasomal activity testing may serve as a useful tool for the diagnosis of CNDLE/PRASS in suspicious cases. Since JAK inhibitors may provide an adequate therapeutic response, it is of great importance to timely diagnose this disease in cases where the genetic results are equivocal. <h3>References</h3> [1]Brehm A, Liu Y, Sheikh A, Marrero B et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest. 2015 Nov 2;125(11):4196-211. [2]Kitamura A, Maekawa Y, Uehara H et al. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest. 2011 Oct;121(10):4150-60. [3]Torrelo A. CANDLE Syndrome As a Paradigm of Proteasome-Related Autoinflammation. Front Immunol. 2017 Aug 9;8:927. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.